Current approaches to facilitate improved drug delivery to the central nervous system.

Although many pharmaceuticals have therapeutic potentials for central nervous system (CNS) diseases, few of these agents have been effectively administered. It is due to the fact that the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSF) restrict them from crossing the brain to exert biological activity. This article reviews the current approaches aiming to improve penetration across these barriers for effective drug delivery to the CNS. These issues are summarized into direct systemic delivery and invasive delivery, including the BBB disruption and convection enhanced delivery. Furthermore, novel drug delivery systems used at the nanoscale, including polymeric nanoparticles, liposomes, nanoemulsions, dendrimers, and micelles are discussed. These nanocarriers could contribute to a breakthrough in the treatment of many different CNS diseases. However, further broadened studies are needed to assess the biocompatibility and safety of these medical devices.

Current Chemical, Biological, and Physiological Views in the Development of Successful Brain-Targeted Pharmaceutics.

One of the greatest challenges with successful pharmaceutical treatments of central nervous system (CNS) diseases is the delivery of drugs into their target sites with appropriate concentrations. For example, the physically tight blood-brain barrier (BBB) effectively blocks compounds from penetrating into the brain, also by the action of metabolizing enzymes and efflux transport mechanisms. However, many endogenous compounds, including both smaller compounds and macromolecules, like amino acids, sugars, vitamins, nucleosides, hormones, steroids, and electrolytes, have their peculiar internalization routes across the BBB. These delivery mechanisms, namely carrier-mediated transport and receptor-mediated transcytosis have been utilized to some extent in brain-targeted drug development. The incomplete knowledge of the BBB and the smaller than a desirable number of chemical tools have hindered the development of successful brain-targeted pharmaceutics. This review discusses the recent advancements achieved in the field from the point of medicinal chemistry view and discusses how brain drug delivery can be improved in the future.

The ALSTER-FLX Registry: 3-Month outcomes after left atrial appendage occlusion using a next-generation device, a matched-pair analysis to EWOLUTION.

BACKGROUND: The new-generation WATCHMAN FLX (Boston Scientific) device for left atrial appendage occlusion has been modified in various aspects to improve procedural results. No comparison of the WATCHMAN FLX device with the previous WATCHMAN device is available. OBJECTIVE: We aimed to compare procedural results with WATCHMAN FLX in patients on dual antiplatelet therapy at ∼3 months with data with WATCHMAN (EWOLUTION [Registry on WATCHMAN Outcomes in Real-Life Utilization]). METHODS: One hundred sixty-four consecutive patients receiving the WATCHMAN FLX device in 4 European centers were included in the retrospective ALSTER-FLX registry. As a control group for a matched-pair analysis, 1020 patients treated with the WATCHMAN device and data up to first follow-up (∼3 months) from EWOLUTION were used. RESULTS: Implantation was successful in all ALSTER-FLX patients (100%) and similar to results in EWOLUTION (99%) (P = .2). We observed no stroke or device embolization in ALSTER-FLX similar to EWOLUTION (stroke 0.5%, device embolization 0.4%) at 3 months. Numerically less ALSTER-FLX patients (2.4%) developed a device-associated thrombus as compared with 3.7% EWOLUTION patients, yet without reaching statistical significance after matching (median [95% confidence interval] device-associated thrombus pairwise event difference 2 [0-6]; P = .1). WATCHMAN FLX implantation was associated with a significant higher sealing rate compared with EWOLUTION at 3 months (ALSTER-FLX 90% vs EWOLUTION 79.4%; P = .039 after matching). Major nonprocedural bleeding events and mortality were similar after matching (median event difference for bleeding 0 [-3 to 3]; P = .6 and death 1 [-2 to 4]; P = .3). CONCLUSION: Periprocedural, early 3-month outcomes with WATCHMAN FLX demonstrate a similar safety profile and an improved sealing rate compared to the WATCHMAN device.

Percutaneous Occlusion of the Left Atrial Appendage with Thrombus Irresponsive to Antithrombotic Therapy.

We analyzed clinical experience with percutaneous closure of instances of left atrial appendage with thrombus (LAAT) irresponsive to antithrombotic therapy in patients treated in three high-volume cardiology centers. Clinical and procedural data regarding consecutive patients who underwent percutaneous left atrial appendage closure (PLAAC) due to LAAT were retrospectively analyzed. The study population consisted of 17 patients (11 men; 68 ± 14 years; CHA2DS2VASC 4.7 ± 1.9; HASBLED 3 (0-5)) with LAAT confirmed by transesophageal echocardiography, and included 5 patients with mechanical heart valves. Most of the patients (94.1%) received anticoagulation therapy before PLAAC. All LAATs were located in distal portions of the appendage and occupied less than 30% of its volume. Occluding-device implantation was successful in 17 patients; in one, a residual leak was disclosed. Appropriate positioning of occluders required more than 1 attempt in 6 individuals (35.3%); in 3 others (17.6%), the subjects' devices had contact with thrombi. No procedural complications were noted. Midterm follow-up (median: 10 months) revealed no procedure-related complications or clinically diagnosed thromboembolism. Transesophageal echocardiography (TEE) performed after six months revealed device-related thrombus in one patient. We concluded that LAAT irresponsive to antithrombotic therapy might be effectively treated with PLAAC, even in patients with mechanical-valve prostheses.

The evaluation of elasticity after nonablative radiofrequency rejuvenation.

BACKGROUND: Laxity and rhytides are manifestations of photodamage on the face and chest. Nonablative radiofrequency (RF) is one of the most common procedures used for skin rejuvenation. AIM: The aim of this study was to assess the elasticity of face and chest skin after multipolar radiofrequency. PATIENTS/METHODS: Thirty women, aged 43-68, were included in the study. Twenty women were postmenopausal and 10 were premenopausal. They received 4 treatment sessions with an application of nonablative radiofrequency in 2-week intervals. Biomechanical properties of the skin were measured with the use of a Cutometer. RESULTS: The objective evaluation in a cutometric analysis showed a statistically significant improvement between measurements taken in the pretreatment period and 3 months after the treatment. CONCLUSIONS: The study is an objective confirmation that RF treatment improves skin elasticity. The method may appear to be beneficial for women of any age and skin types. It is a noninvasive treatment with a low risk of complications.

An evaluation of the antiaging properties of strawberry hydrolysate treatment enriched with L-ascorbic acid applied with microneedle mesotherapy.

BACKGROUND: Mature skin is characterized by a loss of elasticity, hyperpigmentation, and dehydration. L-ascorbic acid stimulates the synthesis of collagen type I, inhibits melanogenesis, and helps to maintain correct skin hydration. Combining microneedle mesotherapy with the application of preparations rich in vitamin C results in better therapeutic effects due to the improved absorption of active substances. The study evaluates the effectiveness of the application of strawberry hydrolysate enriched with L-ascorbic acid using microneedle mesotherapy. MATERIALS AND METHODS: Seventeen volunteers aged 45-70 years underwent a series of four microneedle mesotherapy treatments with vitamin C serum, performed every 10 days. The 20% L-ascorbic acid solution (pH = 3.5) was prepared immediately before application. After the treatment, the participants gave a subjective assessment of the effectiveness. Cutometer® was used to measure skin elasticity and firmness, Corneometer® to measure skin hydration, and Mexameter® skin tone. RESULTS: The results of the survey showed improvements in skin hydration and elasticity. In vivo studies confirmed the effectiveness of serum and the impact of the active substance on skin firmness and elasticity, the degree of hydration and skin tone. CONCLUSION: Microneedling with vitamin C improves skin tone, hydratation and firmness, and decreases the visibility of hyperpigmentation.

Preliminary randomized controlled trial of antiaging effects of l-ascorbic acid applied in combination with no-needle and microneedle mesotherapy.

BACKGROUND: The epidermis is keratinized stratified squamous epithelium covered by hydro-lipid barrier. Vitamin C is a water-soluble antioxidant which protects skin from oxidative damage and rejuvenates photo-aged skin. There are different options of improving active substance penetration through the stratum corneum of the epidermis. One of them is noneedle mesotherapy which is a non-invasive rejuvenation technique involving electric pulses, electroporation, and ultrasounds. The use of these physicals factors results in deeper penetration of active ingredients. The other one is micro-needle mesotherapy which is nonsurgical therapy, which could cause the controlled inflammation. Micro channels are formed by needles during the skin puncture, that facilitate penetration of the active ingredients. AIMS: The aim of the study was to assess the efficacy of L-ascorbic acid applied in combination with no-needle and micro-needle mesotherapy in anti-aging therapy. MATERIALS AND METHODS: This study involved 17 healthy volunteers, 2.5 ml of serum containing 20% L-ascorbic acid with hydrate from strawberries was used topically in every of 4 treatments. No-needle mesotherapy was applied on the left half of the face while microneedle mesotherapy in combination with the same serum was performed on the right half of face. RESULTS: In vivo studies confirmed the effectiveness of both methods. CONCLUSION: The impact of active substance on skin firmness and elasticity as well as the degree of hydration and skin tone was more efficient after micro-needle mesotherapy.